Ketone body modulation of ligand-gated ion channels

Pflanz, Natasha C.; Daszkowski, Anna W.; James, Keith A.; Mihic, S. John

doi:10.1016/j.neuropharm.2018.12.013

Cited by 22 publications

(19 citation statements)

References 61 publications

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“…This means that a higher energy supply (ATP) is required to maintain the high neuronal excitability levels during both the interictal and the ictal phases. Previous studies on ketogenic diets have shown that brain tissue using ketones not only provides more energy but also reduces the excitability of neurons, leading to seizure control (12)(13)(14). Gimenez-Cassina et al (15) confirmed that in the absence of any dietary influence, the selective conversion of brain energy consumption from glucose to ketone body is associated with BAD dependent metabolic transfer and affect the excitability of neurons in patients with epilepsy.…”

Section: Discussionmentioning

confidence: 96%

Cerebral Hemodynamic Evaluation of Main Cerebral Vessels in Epileptic Patients Based on Transcranial Doppler

Meng

2021

Front. Neurol.

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Objective: To study whether there is a difference in peak and mean blood flow velocity between the left and right major cerebral vessels in patients with epilepsy.Methods: Sixteen patients with epilepsy underwent FDG18-PET-CT (PET) scan and electroencephalogram (EEG) examinations. Transcranial Doppler (TCD) was used to detect the peak flow velocity (PFV), mean flow velocity (MFV), and other hemodynamic indicators of bilateral anterior, middle, and posterior cerebral arteries in each patient. According to different patterns of the PET or interictal EEG, the differences in PFV, and MFV of corresponding vessels on both sides under different patterns were compared.Results: According to the PET of the low-metabolism region corresponding to the supplying artery, the PFV and MFV of the supplying artery in the low-metabolism region were lower than the value of the corresponding contralateral vessel. The PFV and MFV on the low metabolic side of PET were lower than that of the corresponding vessels on the opposite side. The PFV and MFV on the discharge side of interictal EEG were also lower than the PFV and MFV of the corresponding vessels on the opposite side. The MFV of posterior cerebral artery on the low metabolic side of PET or the interictal discharge side was significantly different from that of the contralateral vessels (P < 0.05). However, the other aforementioned differences in PFV and MFV did not achieve statistical significance.Conclusion: In epileptic patients, the PFV and MFV of main cerebral vessels on the PET hypometabolized side or the interictal discharge side was lower than that of corresponding vessels on the contralateral side. To some extent, the difference in the MFV of PCA between the bilateral sides can facilitate the lateral diagnosis of the epileptogenic zone.

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Section: Discussionmentioning

confidence: 96%

Cerebral Hemodynamic Evaluation of Main Cerebral Vessels in Epileptic Patients Based on Transcranial Doppler

Meng

2021

Front. Neurol.

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Section: Discussionmentioning

confidence: 99%

“…Ketogenesis is a metabolic process and ketone bodies are acquired from the breakdown of fatty acids ( 46 ). Acetone acts as an inhibitor of glutamate at the excitatory NMDA receptor, while it has little effect on inhibitory GABA receptors ( 46 ). Brain metabolism of ketone bodies provides as much as 30% carbon of glutamate synthesis, which possesses excitotoxicity on neurons ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Acetylation Profiles in the Metabolic Process of Glioma-Associated Seizures

Lin

Zheng

et al. 2021

Front. Neurol.

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Objective: We test the hypothesis that lysine acetylation is involved in the metabolic process of glioma-associated seizures (GAS).Methods: We used label-free mass spectrometry-based quantitative proteomics to quantify dynamic changes of protein acetylation between gliomas with seizure (CA1 group) and gliomas without seizure (CA2 group). Furthermore, differences of acetyltransferase and deacetylase expression between CA1 and CA2 groups were performed by a quantitative proteomic study. We further classified acetylated proteins into groups according to cell component, molecular function, and biological process. In addition, metabolic pathways and protein interaction networks were analyzed. Regulated acetyltransferases and acetylated profiles were validated by PRM and Western blot.Results: We detected 169 downregulated lysine acetylation sites of 134 proteins and 39 upregulated lysine acetylation sites of 35 proteins in glioma with seizures based on acetylome. We detected 407 regulated proteins by proteomics, from which ACAT2 and ACAA2 were the differentially regulated enzymes in the acetylation of GAS. According to the KEGG analysis, the upregulated acetylated proteins within the PPIs were mapped to pathways involved in the TCA cycle, oxidative phosphorylation, biosynthesis of amino acids, and carbon metabolism. The downregulated acetylated proteins within the PPIs were mapped to pathways involved in fatty acid metabolism, oxidative phosphorylation, TCA cycle, and necroptosis. Regulated ACAT2 expression and acetylated profiles were validated by PRM and Western blot.Conclusions: The data support the hypothesis that regulated protein acetylation is involved in the metabolic process of GAS, which may be induced by acetyl-CoA acetyltransferases.

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“…Glycine itself was reported to be an antioxidant and protective of pancreatic cells in diabetic rats (Chen et al, 2018), the effects of glycine on glucose homeostasis (but not vice versa) have recently been reviewed (Yan-Do and MacDonald, 2017). Ketone bodies have been shown to modulate ligand-gated in channel function, with β-hydroxybutyrate at physiological concentrations being an inhibitor of GlyRs expressed on Xenopus oocytes (Pflanz et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Glycine Receptor-Mediated Pain Signaling in vitro and in vivo by Glucose

Hussein

Ahmed

Breitinger

2019

Front. Mol. Neurosci.

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The inhibitory glycine receptor (GlyR) plays an important role in rapid synaptic inhibition in mammalian spinal cord, brainstem, higher brain centers, and is involved in transmission of nociceptive signals. Glucose and related mono- and disaccharides potentiate currents mediated by recombinant α1, α1-β, and α3 GlyRs. Here, we confirmed the specific potentiation of α3 GlyR signaling by glucose through: (i) patch-clamp electrophysiology on recombinant receptors; and (ii) by verifying in vitro data in a mouse model in vivo. Mice were intraperitoneally (IP) injected with glucose (2 g/kg) or vehicle, and then challenged with sublethal doses of strychnine (0.2 mg/kg and 0.5 mg/kg). Pain-related behavior was assessed using two established models: (i) touch sensitivity tests using von Frey filaments; and (ii) hotplate assay. We observed a reduction of pain sensitivity in glucose-treated mice relative to vehicle-treated control mice. Injection of strychnine resulted in an increased sensitivity to tactile and heat stimuli, which was reversed in the presence of glucose. Analgesic effects of glucose were more pronounced in von Frey experiments, consistent with the established use of this model for neuropathic pain. Overall, glucose showed mild analgesic effects and was able to compensate for strychnine-induced allodynia in mice. Since the action of strychnine is specific for GlyR, these experiments show for the first time an in vivo potentiation of GlyR activity by glucose and suggest a molecular mechanism for glucose-mediated analgesia.

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Ketone body modulation of ligand-gated ion channels

Cited by 22 publications

References 61 publications

Cerebral Hemodynamic Evaluation of Main Cerebral Vessels in Epileptic Patients Based on Transcranial Doppler

Cerebral Hemodynamic Evaluation of Main Cerebral Vessels in Epileptic Patients Based on Transcranial Doppler

Acetylation Profiles in the Metabolic Process of Glioma-Associated Seizures

Modulation of Glycine Receptor-Mediated Pain Signaling in vitro and in vivo by Glucose

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